This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The NOS family is a key target for development of new pharmaceuticals for a wide range of diseases that currently lack effective treatments including stroke, septic shock, hypertension and cancer. However, due to an incomplete understanding of the molecular mechanisms of NOS regulation, NOS inhibitors have not yet been available for clinical treatments. The proposed studies will significantly improve the fundamental understanding of NOS regulation, and has the potential of facilitating bio-rational development of new selective mechanism-based drug entities to target these clinically important NOS isoforms.